MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Author:

Wit Jan M,Oostdijk Wilma,Losekoot Monique,van Duyvenvoorde Hermine A,Ruivenkamp Claudia A L,Kant Sarina G

Abstract

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD areGH1andGHRHRdefects, but several novel causes have recently been found, such asGHSR,RNPC3, andIFT172mutations. Besides well-defined causes of GH insensitivity (GHR,STAT5B,IGFALS,IGF1defects), disorders of NFκB signalling,STAT3andIGF2have recently been discovered. HeterozygousIGF1Rdefects are a relatively frequent cause of prenatal and postnatal growth retardation.TRHAmutations cause a syndromic form of short stature with elevated T3/T4ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. HeterozygousNPR2orSHOXdefects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Publisher

Bioscientifica

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism

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